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Open Access Highly Accessed Review

Human Immunodeficiency Virus gag and protease: partners in resistance

Axel Fun1, Annemarie MJ Wensing1, Jens Verheyen2 and Monique Nijhuis1*

Author Affiliations

1 Department of Virology, Medical Microbiology, University Medical Center Utrecht, HP G04.614, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands

2 Institute of Virology, University of Cologne, Cologne, Germany

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Retrovirology 2012, 9:63  doi:10.1186/1742-4690-9-63

Published: 6 August 2012

Abstract

Human Immunodeficiency Virus (HIV) maturation plays an essential role in the viral life cycle by enabling the generation of mature infectious virus particles through proteolytic processing of the viral Gag and GagPol precursor proteins. An impaired polyprotein processing results in the production of non-infectious virus particles. Consequently, particle maturation is an excellent drug target as exemplified by inhibitors specifically targeting the viral protease (protease inhibitors; PIs) and the experimental class of maturation inhibitors that target the precursor Gag and GagPol polyproteins. Considering the different target sites of the two drug classes, direct cross-resistance may seem unlikely. However, coevolution of protease and its substrate Gag during PI exposure has been observed both in vivo and in vitro. This review addresses in detail all mutations in Gag that are selected under PI pressure. We evaluate how polymorphisms and mutations in Gag affect PI therapy, an aspect of PI resistance that is currently not included in standard genotypic PI resistance testing. In addition, we consider the consequences of Gag mutations for the development and positioning of future maturation inhibitors.

Keywords:
HIV; Particle maturation; Protease inhibitors; Maturation inhibitors; Gag mutations; Resistance; Cross-resistance